Towards a European health research and innovation cloud (HRIC).

The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrastructure. Creating a European Health Research and Innovation Cloud (HRIC) within this environment should enable data sharing and analysis for health research across the EU, in compliance with data protection legislation while preserving the full trust of the participants. Such a HRIC should learn from and build on existing data infrastructures, integrate best practices, and focus on the concrete needs of the community in terms of technologies, governance, management, regulation, and ethics requirements. Here, we describe the vision and expected benefits of digital data sharing in health research activities and present a roadmap that fosters the opportunities while answering the challenges of implementing a HRIC. For this, we put forward five specific recommendations and action points to ensure that a European HRIC: i) is built on established standards and guidelines, providing cloud technologies through an open and decentralized infrastructure; ii) is developed and certified to the highest standards of interoperability and data security that can be trusted by all stakeholders; iii) is supported by a robust ethical and legal framework that is compliant with the EU General Data Protection Regulation (GDPR); iv) establishes a proper environment for the training of new generations of data and medical scientists; and v) stimulates research and innovation in transnational collaborations through public and private initiatives and partnerships funded by the EU through Horizon 2020 and Horizon Europe.

Quantifying realized inbreeding in wild and captive animal populations.

Most molecular measures of inbreeding do not measure inbreeding at the scale that is most relevant for understanding inbreeding depression-namely the proportion of the genome that is identical-by-descent (IBD). The inbreeding coefficient FPed obtained from pedigrees is a valuable estimator of IBD, but pedigrees are not always available, and cannot capture inbreeding loops that reach back in time further than the pedigree. We here propose a molecular approach to quantify the realized proportion of the genome that is IBD (propIBD), and we apply this method to a wild and a captive population of zebra finches (Taeniopygia guttata). In each of 948 wild and 1057 captive individuals we analyzed available single-nucleotide polymorphism (SNP) data (260 SNPs) spread over four different genomic regions in each population. This allowed us to determine whether any of these four regions was completely homozygous within an individual, which indicates IBD with high confidence. In the highly nomadic wild population, we did not find a single case of IBD, implying that inbreeding must be extremely rare (propIBD=0-0.00094, 95% CI). In the captive population, a five-generation pedigree strongly underestimated the average amount of realized inbreeding (FPed=0.013

Identification and characterization of a defective CYP3A4 genotype in a kidney transplant patient with severely diminished tacrolimus clearance.

Cytochrome P450 3A4 (CYP3A4) is a major drug-metabolizing enzyme that is widely investigated. So far, no homozygous inactive variant has been described. We report on a 19-year-old kidney transplant patient suffering from Alport syndrome, who experienced unexpected high tacrolimus plasma trough levels during immunosuppressant therapy. Because nonadherence, liver failure, or drug-drug interactions could be excluded, we hypothesized a diminished metabolism of the drug caused by mutations in the main detoxification enzyme, CYP3A4. Exome sequencing revealed a novel single-nucleotide polymorphism (c.802C>T) resulting in a premature stop codon in CYP3A4 exon 5. Accordingly, no CYP3A4 protein could be detected in kidney biopsy tissue, and there was lack of expression in HepG2 cells transiently transfected with the mutated CYP3A4. In addition, the patient harbored inactive CYP3A5*3, resulting in loss of function of the entire CYP3A locus, explaining the deteriorated tacrolimus clearance. This is, to our knowledge, the first case of a complete failure of CYP3A4 in humans.